Sex differences in microRNA expression in first and third trimester human placenta

Abstract

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be the result of sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing was used to identify miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n=113) and parturition (n=47). Sequencing and differential expression (DE) analysis identified 432 mature miRNAs expressed in the first trimester female, 425 in the first trimester male, 400 in the third trimester female, and 508 in the third trimester male placenta (baseMean >10). Of these, 11 sexually dimorphic (FDR<0.05, baseMean >10) miRNAs were identified in the first and 4 miRNAs were identified in the third trimester, including miR-361-5p, significant in both trimesters, all upregulated in females. Across gestation, 207 miRNAs were DE across gestation, common to both females and males, miR-4483, the most DE across gestation. There were twice as many female-specific differences across gestation as male-specific (44 miRNAs vs 21 miRNAs), indicating that miRNA abundance across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex independent and sex specific placenta miRNA atlas across gestation which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.

Sex at the interface: the origin and impact of sex differences in the developing human placenta

“…In the first trimester, miRNA expression from C14MC was represented in males and C19MC was more represented in females. This trend was reversed in the third trimester [36]. Overall in first and third trimester, the current collection of observations suggest that microR-NAs are a consistent hub of sex differences throughout gestation and are linked to cell signaling, growth, cancer, and immune function pathways.…”

“…Six of these miRNAs [4 first trimester, 2 third trimester] had loci on the X chromosome, but the majority were on autosomes. Greater sexual dimorphism was present in the first trimester and one X-linked miRNA, miR-361-5p, was significant in both the first and third trimester [36]. While the sexually dimorphic microRNAs that have been detected in placenta are mostly located in autosomal loci, the highest density (10%) of human microRNAs are located on the X chromosome.…”

“…Several groups have performed transcriptomic profiling of the first-trimester human placenta (reviewed by Yong and Chan [32], 2020: Table 1), however fetal sex as a variable in these datasets is often left unreported or, if reported, is not directly analyzed. In the recent years, four studies have examined fetal sex in early human placental development (Table 1) [33][34][35][36]. In the following sections, we review these findings and consider the evidence for the genetic, hormonal and immune mechanisms that are theorized to account for sex differences in early human placenta and highlight the cellular and molecular processes that are most likely to be impacted by fetal sex.…”

“…It is possible that an X dosage effect may contribute to observed sex differences as well [98]. Comparative analysis of first versus third-trimester placenta in female only and male only cohorts found 52 female exclusive and 32 male exclusive miRNAs differentially expressed across gestation, including miRNAs from the placenta-specific clusters, C14MC and C19MC [36]. These clusters are large, imprinted miRNAs whose members are principally expressed in placenta, and are maternally and paternally expressed, respectively [99].…”